Interactive Effects of -Opioid and Adrenergic- Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine

Samuel Obeng, Departments of Pharmacodynamics (S.O., A.P., J.D.Z.G., L.C.D.S., L.F.R., L.R.G-J., N.P.H., M.P.G.C., V.L.C.P., J.A.H., S.K.S., L.R.M., J.L.W., T.H.), Medicinal Chemistry (S.O., F.L., C.R.M.), and Pharmaceutics (C.R.M.), and Translational Drug Development Core (C.R.M.), Clinical and Translational Sciences Institute, College of Pharmacy, University of Florida, Gainesville, Florida; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (F.L.); Department of Psychology, Louisiana State University, Baton Rouge, Louisiana (P.L.S.), Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Amarillo, Texas (L.R.M., J.L.W., T.H.); Department of Pharmaceutical, Social and Administrative Sciences, McWhorter School of Pharmacy, Samford University, Birmingham, Alabama (S.O.); Department of Pharmacology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health San Antonio, San Antonio, Texas (T.H.).
Francisco Leon, Departments of Pharmacodynamics (S.O., A.P., J.D.Z.G., L.C.D.S., L.F.R., L.R.G-J., N.P.H., M.P.G.C., V.L.C.P., J.A.H., S.K.S., L.R.M., J.L.W., T.H.), Medicinal Chemistry (S.O., F.L., C.R.M.), and Pharmaceutics (C.R.M.), and Translational Drug Development Core (C.R.M.), Clinical and Translational Sciences Institute, College of Pharmacy, University of Florida, Gainesville, Florida; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (F.L.); Department of Psychology, Louisiana State University, Baton Rouge, Louisiana (P.L.S.), Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Amarillo, Texas (L.R.M., J.L.W., T.H.); Department of Pharmaceutical, Social and Administrative Sciences, McWhorter School of Pharmacy, Samford University, Birmingham, Alabama (S.O.); Department of Pharmacology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health San Antonio, San Antonio, Texas (T.H.).
Avi Patel, Departments of Pharmacodynamics (S.O., A.P., J.D.Z.G., L.C.D.S., L.F.R., L.R.G-J., N.P.H., M.P.G.C., V.L.C.P., J.A.H., S.K.S., L.R.M., J.L.W., T.H.), Medicinal Chemistry (S.O., F.L., C.R.M.), and Pharmaceutics (C.R.M.), and Translational Drug Development Core (C.R.M.), Clinical and Translational Sciences Institute, College of Pharmacy, University of Florida, Gainesville, Florida; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (F.L.); Department of Psychology, Louisiana State University, Baton Rouge, Louisiana (P.L.S.), Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Amarillo, Texas (L.R.M., J.L.W., T.H.); Department of Pharmaceutical, Social and Administrative Sciences, McWhorter School of Pharmacy, Samford University, Birmingham, Alabama (S.O.); Department of Pharmacology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health San Antonio, San Antonio, Texas (T.H.).
Julio D. Zuarth Gonzalez, Departments of Pharmacodynamics (S.O., A.P., J.D.Z.G., L.C.D.S., L.F.R., L.R.G-J., N.P.H., M.P.G.C., V.L.C.P., J.A.H., S.K.S., L.R.M., J.L.W., T.H.), Medicinal Chemistry (S.O., F.L., C.R.M.), and Pharmaceutics (C.R.M.), and Translational Drug Development Core (C.R.M.), Clinical and Translational Sciences Institute, College of Pharmacy, University of Florida, Gainesville, Florida; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (F.L.); Department of Psychology, Louisiana State University, Baton Rouge, Louisiana (P.L.S.), Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Amarillo, Texas (L.R.M., J.L.W., T.H.); Department of Pharmaceutical, Social and Administrative Sciences, McWhorter School of Pharmacy, Samford University, Birmingham, Alabama (S.O.); Department of Pharmacology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health San Antonio, San Antonio, Texas (T.H.).
Lucas Chaves Da Silva, Departments of Pharmacodynamics (S.O., A.P., J.D.Z.G., L.C.D.S., L.F.R., L.R.G-J., N.P.H., M.P.G.C., V.L.C.P., J.A.H., S.K.S., L.R.M., J.L.W., T.H.), Medicinal Chemistry (S.O., F.L., C.R.M.), and Pharmaceutics (C.R.M.), and Translational Drug Development Core (C.R.M.), Clinical and Translational Sciences Institute, College of Pharmacy, University of Florida, Gainesville, Florida; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (F.L.); Department of Psychology, Louisiana State University, Baton Rouge, Louisiana (P.L.S.), Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Amarillo, Texas (L.R.M., J.L.W., T.H.); Department of Pharmaceutical, Social and Administrative Sciences, McWhorter School of Pharmacy, Samford University, Birmingham, Alabama (S.O.); Department of Pharmacology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health San Antonio, San Antonio, Texas (T.H.).
Luis F. Restrepo, Departments of Pharmacodynamics (S.O., A.P., J.D.Z.G., L.C.D.S., L.F.R., L.R.G-J., N.P.H., M.P.G.C., V.L.C.P., J.A.H., S.K.S., L.R.M., J.L.W., T.H.), Medicinal Chemistry (S.O., F.L., C.R.M.), and Pharmaceutics (C.R.M.), and Translational Drug Development Core (C.R.M.), Clinical and Translational Sciences Institute, College of Pharmacy, University of Florida, Gainesville, Florida; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (F.L.); Department of Psychology, Louisiana State University, Baton Rouge, Louisiana (P.L.S.), Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Amarillo, Texas (L.R.M., J.L.W., T.H.); Department of Pharmaceutical, Social and Administrative Sciences, McWhorter School of Pharmacy, Samford University, Birmingham, Alabama (S.O.); Department of Pharmacology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health San Antonio, San Antonio, Texas (T.H.).
Lea R. Gamez-Jimenez, Departments of Pharmacodynamics (S.O., A.P., J.D.Z.G., L.C.D.S., L.F.R., L.R.G-J., N.P.H., M.P.G.C., V.L.C.P., J.A.H., S.K.S., L.R.M., J.L.W., T.H.), Medicinal Chemistry (S.O., F.L., C.R.M.), and Pharmaceutics (C.R.M.), and Translational Drug Development Core (C.R.M.), Clinical and Translational Sciences Institute, College of Pharmacy, University of Florida, Gainesville, Florida; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina (F.L.); Department of Psychology, Louisiana State University, Baton Rouge, Louisiana (P.L.S.), Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Amarillo, Texas (L.R.M., J.L.W., T.H.); Department of Pharmaceutical, Social and Administrative Sciences, McWhorter School of Pharmacy, Samford University, Birmingham, Alabama (S.O.); Department of Pharmacology, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health San Antonio, San Antonio, Texas (T.H.).
Nicholas P. Ho

Abstract

The primary kratom alkaloid mitragynine is proposed to act through multiple mechanisms, including actions at -opioid receptors (MORs) and adrenergic- receptors (A Rs), as well as conversion in vivo to a MOR agonist metabolite (i.e., 7-hydroxymitragynine). A R and MOR agonists can produce antinociceptive synergism. Here, contributions of both receptors to produce mitragynine-related effects were assessed by measuring receptor binding in cell membranes and, in rats, pharmacological behavioral effect antagonism studies. Mitragynine displayed binding affinity at both receptors, whereas 7-hydroxymitragynine only displayed MOR binding affinity. Compounds were tested for their capacity to decrease food-maintained responding and rectal temperature and to produce antinociception in a hotplate test. Prototypical MOR agonists and 7-hydroxymitragynine, but not mitragynine, produced antinociception. MOR agonist and 7-hydroxymitragynine rate-deceasing and antinociceptive effects were antagonized by the opioid antagonist naltrexone but not by the A R antagonist yohimbine. Hypothermia only resulted from reference A R agonists. The rate-deceasing and hypothermic effects of reference A R agonists were antagonized by yohimbine but not naltrexone. Neither naltrexone nor yohimbine antagonized the rate-decreasing effects of mitragynine. Mitragynine and 7-hydroxymitragynine increased the potency of the antinociceptive effects of A R but not MOR reference agonists. Only mitragynine produced hypothermic effects. Isobolographic analyses for the rate-decreasing effects of the reference A R and MOR agonists were also conducted. These results suggest mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with A R and MOR agonists. When combined with A R agonists, mitragynine could also produce hypothermic synergism. SIGNIFICANCE STATEMENT: Mitragynine is proposed to target the µ-opioid receptor (MOR) and adrenergic-α receptor (AαR) and to produce behavioral effects through conversion to its MOR agonist metabolite 7-hydroxymitragynine. Isobolographic analyses indicated supra-additivity in some dose ratio combinations. This study suggests mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with AαR and MOR agonists. When combined with AαR agonists, mitragynine could also produce hypothermic synergism.